کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1950616 | 1055673 | 2014 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Oxidative stress impairs multiple regulatory events to drive persistent cytokine-stimulated STAT3 phosphorylation
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کلمات کلیدی
STAT3SOCS3NLSFCSTC-PTPGFPMEFOSMCLSMLIFnESJanus kinase - کیناز جانوس MAPK - MAPKHydrogen peroxide - آب اکسیژنهSTAT - آمارoncostatin M - اوکتواستاتین مOxidative stress - تنش اکسیداتیوNuclear export sequence - توالی صادرات هسته ایnuclear localisation sequence - توالی محلی سازی هسته ایNuclear transport - حمل و نقل هسته ایstandard error of the mean - خطای استاندارد میانگینfoetal calf serum - سرم گوساله جنینsuppressor of cytokine signalling 3 - سرکوب سیگنالینگ سیتوکین 3Cytokines - سیتوکین هاleukemia inhibitory factor - عامل مهارکننده لوکمیmurine embryonic fibroblast - فیبروبلاست جنینی جنینیSignal transducer and activator of transcription - مبدل سیگنال و فعال کننده رونویسیSEM - مدل معادلات ساختاری / میکروسکوپ الکترونی روبشیconfocal laser scanning microscopy - میکروسکوپهای اسکن لیزری کانفوکالH2O2 - هیدروژن پراکسیدT-cell protein tyrosine phosphatase - پروتئین T-cell tyrosine phosphatasegreen fluorescent protein - پروتئین فلورسنت سبزmitogen-activated protein kinase - پروتئین کیناز فعال با mitogenJAK - چگونه
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
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چکیده انگلیسی
Although cytokine-driven STAT3 phosphorylation and activation are often transient, persistent activation of STAT3 is a hallmark of a range of pathologies and underpins altered transcriptional responses. As triggers in disease frequently include combined increases in inflammatory cytokine and reactive oxygen species levels, we report here how oxidative stress impacts on cytokine-driven STAT3 signal transduction events. In the model system of murine embryonic fibroblasts (MEFs), combined treatment with the interleukin-6 family cytokine Leukemia Inhibitory Factor (LIF) and hydrogen peroxide (H2O2) drove persistent STAT3 phosphorylation whereas STAT3 phosphorylation increased only transiently in response to LIF alone and was not increased by H2O2 alone. Surprisingly, increases in transcript levels of the direct STAT3 gene target SOCS3 were delayed during the combined LIF + H2O2 treatment, leading us to probe the impact of oxidative stress on STAT3 regulatory events. Indeed, LIF + H2O2 prolonged JAK activation, delayed STAT3 nuclear localisation, and caused relocalisation of nuclear STAT3 phosphatase TC-PTP (TC45) to the cytoplasm. In exploring the nuclear import/export pathways, we observed disruption of nuclear/cytoplasmic distributions of Ran and importin-α3 in cells exposed to H2O2 and the resultant reduced nuclear trafficking of classical importin-α/β-dependent protein cargoes. CRM1-mediated nuclear export persisted despite the oxidative stress insult, with sustained STAT3 Y705 phosphorylation enhancing STAT3 nuclear residency. Our studies thus reveal for the first time the striking impact of oxidative stress to sustain STAT3 phosphorylation and nuclear retention following disruption of multiple regulatory events, with significant implications for STAT3 function.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research - Volume 1843, Issue 3, March 2014, Pages 483-494
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research - Volume 1843, Issue 3, March 2014, Pages 483-494
نویسندگان
Ivan H.W. Ng, Yvonne Y.C. Yeap, Lynette S.R. Ong, David A. Jans, Marie A. Bogoyevitch,